Acyl glucuronides-mediators of drug-induced toxicities?

被引:2
|
作者
Baillie, Thomas A. [1 ]
机构
[1] Univ Washington, Sch Pharm, Dept Med Chem, Seattle, WA 98195 USA
关键词
Acyl glucuronides; reactive metabolites; bioactivation; toxicity; drug safety; XENOBIOTIC CARBOXYLIC-ACIDS; LIVER-INJURY; IN-VITRO; METABOLIC-ACTIVATION; COVALENT BINDING; PROTEIN ADDUCTS; DICLOFENAC; REACTIVITY; IDENTIFICATION; BIOACTIVATION;
D O I
10.1007/s00044-023-03062-6
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The role of acyl glucuronide (AG) metabolites as mediators of drug-induced toxicities remains controversial, in part due to difficulties in studying this group of reactive drug conjugates. Confounding factors include the bioactivation of carboxylic acid drugs by alternative pathways, AG-mediated inhibition of key enzymes and transporters, and unanticipated interactions with several biological systems. These issues, together with the inherent instability of AGs under physiological conditions, have led to significant challenges in assessing the human safety of AGs according to current regulatory guidances. Despite important advances in the analytical methodology used to detect, identify and quantify AGs in biological fluids and tissues, there is a lack of information on the molecular mechanisms that underlie the toxicity of carboxylic acid-containing drugs and their AG metabolites. This review summarizes the current status of the field, and the de-risking strategies that have been adopted to minimize the likelihood of AG-mediated toxicity in drug discovery and lead optimization programs.
引用
收藏
页码:1249 / 1262
页数:14
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